Although the risk of breast cancer for women in the U.S. is approximately 1 in 9, identification of risk factors and translation of that knowledge into strategies for prevention have been inhibited by poor understanding of disease pathogenesis. A few benign breast proliferations are associated with higher risk of breast cancer but definition of a preneoplastic morphologic continuum is lacking. The investigators propose to study 5353 eligible women, derived from a large multi-ethnic population, diagnosed by biopsy with benign breast disease between 1981-1991, followed from 5-15 years, and yielding an estimated 248 women who will have developed invasive breast cancer. The overall aims are to 1) ascertain the incidence and time span of breast cancer development in this cohort, 2) to estimate the frequency of selected genetic alterations in both benign breast disease (BBD) and invasive cancers from the same individuals in a subset of the cohort and 3) using a nested case-control approach, to evaluate risk factors for breast cancer among women with BBD, including specific histological characteristics, molecular markers, family history of breast cancer, and reproductive history. The purpose of the study is to evaluate the importance of biomarkers for risk for breast cancer development and determination of their contribution to definition of a genetic sequence in breast carcinogenesis. Assessment of genetic alterations will employ florescent in situ hybridization and the polymerase chain reaction (PCR). The PI will identify chromosomal aneuploidy, selective with respect to individual chromosomes and as a measure of DNA ploidy, and HER-2/neu amplification patterns in BBD and invasive cancer. The PI will identify p53 mutations by single strand conformation analysis (SSCP), determine clonality using the PCR nested primer approach for the PGK locus (on Xq arm), and assess loss of heterozygosity (LOH) for intragenic markers of the BRCA1 (17q21) and E-cadherin (16q22) genes. When LOH is observed, analysis of the genes using SSCP will attempt to identify the putative mutations. Lack of a constitutional BRCA1 mutation will rule out one form of inherited breast cancer, allowing subtyping of the remaining tumors by histopathological and genetic profiles, and time frame of cancer development. This study should help establish a genetic and morphologic continuum from BBD to breast cancer and provide a firmer basis for interpretation of the roles of known risk factors, with the eventual objective of permitting targeted testing of preventive strategies and therapeutic regimens.
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